Impact of diabetes mellitus on outcome of HCC

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					                                               Annals of Hepatology 2008; 7(2): April-June: 148-151

                                                               Original Article

    Hepatology      Impact of diabetes mellitus on outcome of HCC
                                    Deepak N. Amarapurkar;1 Nikhil D. Patel;2 Praful M. Kamani2

Abstract                                                                    Key words: Hepatocellular carcinoma, Diabetes Mellitus,
                                                                            Non-alcoholic fatty liver disease, Chronic liver disease.
Background: Diabetes mellitus (DM) is recently identi-
fied risk factor for development and progression of                         Introduction
chronic liver disease as well as hepatocellular carcino-
ma (HCC). We planned a prospective analysis to identi-                          Type-2 diabetes mellitus (DM) increases risk of develop-
fy impact of DM in Indian patients with HCC. Methods:                       ment of chronic liver disease (CLD).1 Commonest CLD in
During last 10 years, 160 consecutive patients of HCC                       DM is non-alcoholic fatty liver disease (NAFLD).2 Hepato-
were evaluated. Demographic profile like age of presen-                     cellular carcinoma (HCC) occurs in patients with CLD and
tation, clinical features, etiology of HCC, tumor size at                   mostly in presence of cirrhosis. Known predisposing causes
presentation, management and ultimate outcome was                           of HCC are hepatitis B virus, hepatitis C virus (HCV),
compared diabetic with non-diabetic HCC patients. Re-                       chronic alcohol abuse, hemochromatosis and, recently, non-
sults: During last 10 years, 160 consecutive patients of                    alcoholic fatty liver disease (NAFLD).3 Cryptogenic cirrho-
HCC were evaluated (Mean age = 59.6 ± 12.9 years, sex                       sis remains responsible for HCC in 15-50% cases.4,5
ratio (M: F) = 5.4: 1). Etiology for HCC were hepatitis B                       Although earlier studies denied the association be-
in 45 (28.2%), hepatitis C in 18 (11.3%), alcohol in 27                     tween type-2 diabetes mellitus (DM) and HCC;6-8 in most
(16.8%), alcohol with hepatitis B in 12 (7.5%), alcohol                     of the recent studies, DM is shown to increase risk of HCC
with hepatitis C in 1 (0.6%), non-alcoholic steatohepati-                   by 2- to 4-fold, even after adjusting for other predisposing
tis in 4 (2.5%) and cryptogenic in 53 (33.2%) patients.                     factors.5,9-29 In presence of viral hepatitis and alcohol in-
Patients of HCC with DM (group-A, n =46, age = 62.6 ±                       take, DM increases risk for HCC by 10-fold.25 DM is a ma-
9.5 years, sex (M: F) = 6.6:1) were compared with pa-                       jor risk factor for NAFLD,30-33 which is shown to predis-
tient of HCC without DM (group-B, n =114, age = 66.7 ±                      pose for cryptogenic cirrhosis34 and HCC.35-37 There is in-
13.7 years, sex (M: F) = 5.4:1). Duration of diabetes in                    creased incidence of DM in HCV infection, a known risk
group-A was 7.6 ± 3.2 years. Patients in group-A had                        factor for HCC. Cirrhosis itself is diabetogenic state and
more advanced HCC (size of lesion > 5 cm and >3 le-                         also a predisposition for HCC. Diabetes is a risk factor, if
sions of 3 cm or more diameter, portal vein thrombosis                      not actually etiologic for HCC, but temporal relationship
or intra-hepatic bile duct involvement) than group-B [34                    is not yet clearly defined.9,27 Only few studies have shown
(73.9%) vs 72 (54.3%)]. Mortality with in one year was                      DM to precede HCC.1,38 World-wide, incidence of DM as
significantly more in group-A compared to group-B [36                       well as HCC is increasing.1 India is experiencing an epi-
(78.2%) vs 56 (49.1%)]. Conclusion: DM is associated                        demic of DM.39 Establishing epidemiological relation and
with more advanced lesion and poor outcome in patient                       cause-effect relationship between these two is important.
with HCC.                                                                       There are only few studies on impact of DM on man-
                                                                            agement and outcome of HCC. None of the studies from
    Head.                                                                   India have shown relation of DM with HCC. This study
    Clinical assistants, Gastroenterology Department, Bombay                was planned to evaluate impact of DM on management
    Hospital and Medical Research Centre, Mumbai.                           and outcome of HCC.
Address for correspondence:
Dr. Deepak Amarapurkar                                                      Materials and methods
D 401/402 Ameya RBI Employees
Co-Op Housing Society,                                                         This case-control observational study was carried out
Plot No. 947-950
New Prabhadevi Road
                                                                            over study period of 10 years (1997-2006) on all the con-
Prabhadevi                                                                  secutive patients of HCC. Diagnosis of HCC was based on
Mumbai 400 025                                                              hyper-vascular tumor in the liver on two imaging studies
Telephone No. 91 22 24306262/24222432                                       or hyper-vascular tumor on single imaging modality with
Fax No. 91 22 24368623
                                                                            serum alpha-fetoprotein level greater than 400 ng/dL.
                                                                               Patients were divided into 2 groups: a) Diabetic pa-
Manuscript received and accepted: 25 April 2008                             tients with HCC and b) Non-diabetic patients with HCC.
                                           DN Amarapurkar et al. Impact of diabetes mellitus on outcome of HCC                               149

Diabetes was diagnosed according to American Diabetes                           Discussion
Association criteria on the basis of use of oral hypogly-
cemic drugs; fasting plasma glucose level ≥ 126 mg/dL;                              Previously, DM is shown to be a bad prognostic factor
2-hour plasma glucose ≥ 200 mg/dL during oral glucose                           for long-term survival of cirrhotic patients and mortality
tolerance test; and/or random or 2-hour post-prandial                           mainly being related to liver failure.40
plasma glucose level ≥ 200 mg/dL.                                                   Among 7 studies done to find out impact of DM on
   In both groups following features were noted: age of                         HCC management, with few exceptions, most have
presentation, clinical features, laboratory features, Child                     shown increased post-resection complications and de-
class (CPT score), etiology (hepatitis B, hepatitis C, alco-                    creased post-resection survival, most probably due to in-
hol, NASH or other etiologies), tumor characteristics at                        creased risk of hepatic decompensation in DM.41-47 In our
presentation (advanced HCC), management (resection                              study, DM is associated with morphologically advanced
and ablative therapy or palliative management) and sur-                         lesions and with advanced liver disease regardless of eti-
vival. Advanced HCC (morphological) was diagnosed on                            ology. This can be a deciding factor for delineating man-
basis of tumor size > 5 cm or > 3 tumors each measuring >                       agement strategies, namely surgical resection, percutane-
3 cm diameter or portal vein thrombosis or bile duct in-                        ous therapies and trans-arterial chemoembolization. Our
vasion.                                                                         study also shows that DM has adverse prognosis in HCC
   Statistical analysis was performed using Chi square                          with high 1-year mortality rate.
test and student t test.                                                            It is still unclear whether HCC occurs because of insu-
                                                                                lin resistance, which leads to NASH, which leads to cir-
Results                                                                         rhosis, or whether the stimulatory effects of insulin on
                                                                                hepatocyte growth lead more directly to neoplasia. Re-
    As seen in Table I, majority of the patients in both                        cent studies have thrown light on how DM leads to HCC.
groups were in age group 51-70 years. There was no sta-                         DM is a state of hyperinsulinemia. Hyperinsulinemia
tistically significant difference in both the study groups                      may directly induce HCC: 1. by the up-regulation of re-
regarding age distribution.                                                     ceptors of specific growth factors (insulin and insulin-
    Different etiologies of HCC are tabulated in Table II.                      like-growth factor-1);48,49 2. by activating mitogen acti-
As an etiology for HCC, alcohol and NASH were signifi-                          vated kinase that leads to phosphorylation of insulin re-
cantly higher in group-A.                                                       ceptor substance-1(IRS-1) a key protein involve in
    As seen in Table III, in group-A there was higher child                     cellular proliferation.50,51 Insulin resistance may play a
class C patients and more advanced HCC. Also there was                          role by increasing oxidative stress and generation of reac-
lower rate of curative treatment for HCC. Mortality rates                       tive oxygen species that leads to a. p53 tumor suppressor
at 1-year were higher in group-A.                                               gene mutation via by-product of lipid peroxidation (4-
                                                                                hydroxynoneal),52,53 or b. up-regulation of proinflamma-
                                                                                tory cytokines. Thus, inflammation, cellular prolifera-
                                                                                tion, apoptosis inhibition and tumor suppressor gene mu-
Table I. Age-wise distribution.                                                 tations in setting of advanced liver disease (as a result of
                                                                                insulin resistance and hyperinsulinemia) may lead to
Age in years,        Group A,               Group B,
n (%)                 n = 46                n = 114              p

< 50                  8 (17.4)             17   (14.9)          NS              Table III. Presenting features and outcome of both groups.
51-60                13 (28.3)             28   (24.6)          NS
61-70                19 (41.3)             46   (40.3)          NS                                               Group A,      Group B,
> 70                   6 (13)              23   (20.2)          NS              Parameters                        n = 46        n=114        p

                                                                                Mean age, year               62.6 ± 9.5       66.7 ± 13.7    NS
                                                                                Sex ratio (M:F)                 6.6:1            5.4:1       NS
                                                                                Mean duration of
Table II. Different etiologies of HCC.                                          Diabetes, years               7.6 ± 3.2            ---        -
                                                                                Mean CPT score               11.8 ± 2.6        10.2 ± 2.1    NS
Etiology, n (%)          Group A,        Group B,               Total           Child class C, n (%)         37 (80.4)         70 (61.4)     S
                          n = 46         n = 114         p     n = 160          α-fetoprotein
                                                                                (> 400 ng/dL), n (%)         16 (34.8)         46 (40.3)     NS
Hepatitis B alone        11 (23.9)       34 (29.8)       NS   45 (28.1)         Mean α-fetoprotein,
Hepatitis B with alcohol 6 (13)           6 (5.3)        NS    12 (7.5)         ng/dL                      1864.5 ± 441.5    2309 ± 726.6    NS
Alcohol alone            14 (30.4)       13 (11.4)        S   27 (16.8)         Advanced lesions, n (%)      34 (73.9)         62 (54.3)      S
Hepatitis C alone          2 (4.3)        16 (14)        NS   18 (11.3)         Resection or ablative
Hepatitis C with alcohol    0 (0)         1 (0.9)        NS    1 (0.6)          therapy, n (%)                 4 (8.6)         20 (17.5)     S
NASH                       4 (8.7)         0 (0)          S    4 (2.5)          Mean survival, months        10.1 ± 3.1        18.7 ± 6.1    S
Cryptogenic               9 (19.6)       44 (38.6)        S   53 (33.1)         Mortality at 1-year, n (%)   36 (78.2)         56 (49.1)     S
150                                                       Annals of Hepatology 7(2) 2008: 148-151

HCC formation. Hyperinsulinemia is associated with in-                           21. Wideroff L, Gridley G, Mellemkjaer L, Chow WH, Linet M,
creased risk of HCC as well as it is shown to increase                               Keehn S, et al. Cancer incidence in a population-based cohort of
                                                                                     patients hospitalized with diabetes mellitus in Denmark. J Natl
growth rate of HCC.54,55                                                             Cancer Inst 1997; 89: 1360-1365.
   In conclusion, Diabetic patients with HCC had more                            22. Lagiou P, Kuper H, Stuver S, Tzonou A, Trichopoulos D, Adami
advanced liver failure, morphologically more advanced                                HO. Role of diabetes mellitus in the etiology of hepatocellular
lesions and poorer long-term prognosis compared to non-                              carcinoma. J Natl Cancer Inst 2000; 92: 1096-1099.
                                                                                 23. Fujino Y, Mizoue T, Tokui N, Yoshimura T. Prospective study
diabetic patients with HCC.                                                          of diabetes mellitus and liver cancer in Japan. Diabetes Metab
                                                                                     Res Rev 2001; 17: 374-379.
References                                                                       24. Tazawa J, Maeda M, Nakagawa M, Ohbayashi H, Kusano F,
                                                                                     Yamane M, et al. Diabetes mellitus may be associated with
                                                                                     hepatocarcinogenesis in patients with chronic hepatitis C. Dig Dis
1.    El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of
                                                                                     Sci 2002; 47: 710-715.
      chronic liver disease and hepatocellular carcinoma. Gastroenter-
                                                                                 25. Hassan M, Hwang L, Hatten C, Swaim M, Li D, Abbruzzese J, et
      ology 2004; 126: 460-468.
                                                                                     al. Risk factors for hepatocellular carcinoma: synergism of alco-
2.    Amarapurkar D, Das HS. Chronic liver disease in diabetes melli-
                                                                                     hol with viral hepatitis and diabetes mellitus. Hepatology 2002;
      tus. Tropical Gastroenterol 2002; 23: 3-5.
                                                                                     36: 1206-1213.
3.    Ruhl CE, Everhart JE. Determinants of the association of over-
                                                                                 26. Lai MS, Hsieh MS, Chiu YH, Chen TH. Type 2 diabetes and
      weight with elevated serum alanine aminotransferase activity in
      the United States. Gastroenterology 2003; 124: 71-79.                          hepatocellular carcinoma: a cohort study in high prevalence area
4.    Di Bisceglie AM, Carithers Jr RL, Gores GL. Hepatocellular car-                of hepatitis virus infection. Hepatology 2006; 43: 1295-1302.
      cinoma. Hepatology 1998; 28: 1161-1165.                                    27. Harrison SA. Liver disease in patients with diabetes mellitus. J
5.    El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in               Clin Gastroenterol 2006; 40: 68-76.
      hepatocellular carcinoma: a case-control study among United                28. Kaczynski J, Hansson G, Wallerstedt S. Diabetes: one of few
      States veterans. Am J Gastroenterol 2001; 96: 2462-2467.                       remarkable differences in clinicopathologic features between cir-
6.    Kessler II. Cancer mortality among diabetics. J Natl Cancer Inst               rhotic and noncirrhotic Swedes with hepatocellular carcinoma.
      1970; 44: 2051-2055.                                                           Dig Dis Sci 2006; 51: 796-802.
7.    Ragozzino M, Melton III LJ, Chu CP, Palumbo PJ. Subsequent                 29. Di Bisceglie AM. What every hepatologist should know about
      cancer risk in the incidence cohort of Rochester, Minnesota, resi-             endocrinology: Obesity, diabetes, and liver disease. Gastroenter-
      dents with diabetes mellitus. J Chronic Dis 1982; 35: 13-19.                   ology 2004; 126: 604-606.
8.    Lu SN, Lin TM, Chen CJ, Chen JS, Liaw YF, Chang WY, et al. A               30. Matteoni C, Younossi Z, Gramlich T, Bopari N, Liu Y,
      case-control study of primary hepatocellular carcinoma in Tai-                 McCullough A. Nonalcoholic fatty liver disease: a spectrum of
      wan. Cancer 1988; 62: 2051-2055.                                               clinical and pathological severity. Gastroenterology 1999; 116:
9.    Beasley RP. Diabetes and hepatocellular carcinoma. Hepatology                  1413-1419.
      2006; 44: 1408-1410.                                                       31. Marchesini G, Brizi M, Morselli-Labate A, Bianchi G, Bugianesi
10.   El–Serag HB, Hampel H, Javadi F. The Association Between                       E, McCullough A, et al. Association of nonalcoholic fatty liver
      Diabetes and Hepatocellular Carcinoma: A Systematic Review of                  disease with insulin resistance. Am J Med 1999; 107: 450-455.
      Epidemiologic Evidence. Clin Gastroenterol Hepatol 2006; 4:                32. Belfiore F, Iannello S. Insulin resistance in obesity: metabolic
      369-380.                                                                       mechanisms and measurement methods. Mol Genet Metab 1998;
11.   La Vecchia C, Negri E, D’Avanzo B, Boyle P, Franceschi SD.                     65: 121-128.
      Medical history and primary liver cancer. Cancer Res 1990; 50:             33. Falck-Ytter, Younossi Z, Marchesini G, McCullough A. Clinical
      6274-6277.                                                                     features and natural history of nonalcoholic steatosis syndromes.
12.   La Vecchia C, Negri E, Franceschi SD, D’Avanzo B, Boyle P. A                   Semin Liver Dis 2001; 21: 17-26.
      case-control study of diabetes mellitus and cancer risk. Br J Can-         34. Powell E, Cooksley W, Hanson R, Searle J, Halliday J, Powell L.
      cer 1994; 70: 950-953.                                                         The natural history of nonalcoholic steatohepatitis: a follow-up
13.   La Vecchia C, Negri E, DeCarli A, Franceschi SD. Diabetes mel-                 study of forty-two patients for up to 21 years. Hepatology 1990;
      litus and the risk of primary liver cancer. Int J Cancer 1997; 73:             11: 74-80.
      204-207.                                                                   35. Cotrim H, Parana R, Braga E, Lyra L. Nonalcoholic steatohepatitis
14.   Adami HO, McLaughlin J, Ekbom A, Berne C, Silverman D,                         and hepatocellular carcinoma: natural history? Am J Gastroenterol
      Hacker D, et al. Cancer risk in patients with diabetes mellitus.               2000; 95: 3018-3019.
      Cancer Causes Control 1991; 2: 307-314.                                    36. Zen Y, Katayanagi K, Tsuneyama K, Harada K, Araki I,
15.   Adami HO, Chow WH, Nyren O, Berne C, Linet MS, Ekbom A,                        Nakanuma Y. Hepatocellular carcinoma arising in non-alcoholic
      et al. Excess risk of primary liver cancer in patients with diabetes           steatohepatitis. Pathol Int 2001; 51: 127-131.
      mellitus. J Natl Cancer Inst 1996; 88: 1472-1477.                          37. Shimada M, Hashimoto E, Taniai M, Hasegawa K, Okuda H,
16.   Kingston ME, Ali MA, Atiyeh M, Donnelly RJ. Diabetes mellitus                  Yayashi N, et al. Hepatocellular carcinoma in patients with non-
      in chronic active hepatitis and cirrhosis. Gastroenterology 1984;              alcoholic steatohepatitis. J Hepatol 2002; 37: 154-160.
      87: 688-694.                                                               38. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM
17.   Lawson DH, Gray JM, McKillop C, Clarke J, Lee FD, Patrick RS.                  occurs at least 4–7 years before clinical diagnosis. Diabetes Care
      Diabetes mellitus and primary hepatocellular carcinoma. Q J Med                1992; 15: 815-819.
      1986; 61: 945-955.                                                         39. Iyer SR. Type 2 diabetes mellitus express highway, where is the
18.   Davila JA, Morgan RO, Shaib Y, et al. Diabetes increases the risk              ‘U’ turn? JAPI 2003; 51: 495-500.
      of hepatocellular carcinoma in the United States: a population             40. Bianchi G, Marchesini G, Zoli M, Bugianesi E, Fabbri A, Pisi E.
      based case control study. Gut 2005; 54: 533-539.                               Prognostic significance of diabetes in patients with cirrhosis.
19.   Yu MC, Tong MJ, Govindarajan S, Henderson BE. Non-viral                        Hepatology 1994; 20: 119-25.
      risk factors for hepatocellular carcinoma in a low-risk popula-            41. Huo T-I, Lui W-Y, Huang Y-H, et al. Diabetes mellitus is a risk
      tion, the non-Asians of Los Angeles County, California. J Natl                 factor for hepatic decompensation in patients with hepatocellular
      Cancer Inst 1991; 83: 1820-1826.                                               carcinoma undergoing resection: a longitudinal study. Am J
20.   Braga C, La Vecchia C, Negri E, Franceschi S. Attributable risks               Gastroenterol 2003; 98: 2293-2298.
      for hepatocellular carcinoma in Northern Italy. Eur J Cancer               42. Huo T-I, Wu J-C, Lui W-Y, et al. Differential mechanism and
      1997; 33: 629-634.                                                             prognostic impact of diabetes mellitus on patients with hepato-
                                            DN Amarapurkar et al. Impact of diabetes mellitus on outcome of HCC                                       151

      cellular carcinoma undergoing surgical and nonsurgical treat-                    vation by hepatitis B virus X gene products. Cancer Res 1996;
      ment. Am J Gastroenterol 2004; 99: 1479-1487.                                    56: 3831-36.
43.   Toyoda H, Kumada T, Nakano S, et al. Impact of diabetes melli-             50.   Kaburagi Y, Yamachui T, Yamamoto-Honda R, et al. The mecha-
      tus on the prognosis of patients with hepatocellular carcinoma.                  nism of insulin-induced signal transduction mediated by the insu-
      Cancer 2001; 91: 957-963.                                                        lin receptor substrate family. Endocr J 1999; 56(suppl): 25-34.
44.   Ikeda Y, Shimada M, Hasegawa H, et al. Prognosis of hepatocel-             51.   Tanaka S, Mohr L, Schmidt EV, et al. Biologic effect of human
      lular carcinoma with diabetes mellitus after hepatic resection.                  insulin receptor substrat-1 overexpression in hepatocytes.
      Hepatology 1998; 27: 1567-1571.                                                  Hepatology 1997; 26: 598-604.
45.   Poon RT, Fan ST, Wong J. Does diabetes mellitus influence the              52.   Hu W, Feng Z, Eveleigh J, et al. The major lipid peroxidation
      perioperative outcome or long-term prognosis after resection of                  product, trans-4-hydroxy-2-noneal, preferentially from DNA
      hepatocellular carcinoma? Am J Gastroenterol 2002; 97: 1480-1488.                adduct at codon 249 of human p53gene, a unique mutational
46.   Shimada M, Matsumata T, Akazawa K, et al. Estimation of risk of                  hotspot in hepatocellular carcinoma. Carcinogenesis 2002; 23:
      major complications after hepatic resections. Am J Surg 1994;                    1781-89.
      167: 339-403.                                                              53.   Hsu HC, Peng SY, Lai PL, et al. Allotype loss of heterogeneity of
47.   Yanaga K, Matsumata T, Hayashi H, et al. Effect of diabetes                      p53 in primary and recurrent hepatocellular carcinoma: a stuffy
      mellitus on hepatic resection. Arch Surg 1993; 128: 445-448.                     of 150 patient. Cancer 1994; 73: 42-7.
48.   Moore MA, Park CB, Tsuda H. Implication of the                             54.   Balkau B, Kahn HS, Courbon D, et al. Hyperinsulinemia predicts
      hyperinsulinemia-diabetes-cancer link for preventive effect. Eur                 fatal liver cancer but is inversely associated with fatal cancer at
      J Cancer Prev 1998; 7: 89-107.                                                   some other sites. Diabetes Care 2001; 24: 843-849.
49.   Kim SO, Park GJ, Lee YI. Increased expression of the insulin like          55.   Saito K, Inoue S, Saito T, et al. Augmentation effect of postpran-
      growth factor receptor –I (IGF-1) receptor gene in hepatocellu-                  dial hyperinsulinemia on growth of human hepatocellular carci-
      lar carcinoma cell lines: implication of IGF-I receptor gene acti-               noma. Gut 2002; 51: 100-104.

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